KR100830359B1 - Novel anticholinergic agents that can be used as medicaments, method for the production thereof and a pharmaceutical preparation comprising them - Google Patents

Abstract

The present invention relates to novel anticholinergic agents of formula (I). The present invention also relates to the use of said formulation as a medicament.

Formula 1

In the above formula,

A, X ^- and groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be as defined in the claims and in the specification.

Anticholinergic, asthma, COPD

Description

Novel anticholinergic agents that can be used as medicaments, method for the production Technical and a pharmaceutical preparation comprising them}

The present invention relates to novel anticholinergic agents of the formula (1), their preparation as well as their use as medicaments.

In the above formula,

A, X ^- and groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be as defined in the claims and in the specification.

Anticholinergic agents can be used to produce therapeutic effects in a wide range of diseases. Specific examples include asthma or COPD (chronic obstructive pulmonary disease). To treat this disease, WO 92/16528 proposes anticholinergic agents having a scopin, trophenol or tropin basic structure.

The primary purpose of WO 92/16528 is the preparation of anticholinerically effective compounds characterized by long lasting activity. To achieve this object, WO 92/16528 describes in particular scopine, trophenol or benzyl esters of tropin.

In order to treat chronic diseases, it is often desirable to prepare a medicament with a long active duration. In general, this ensures that the concentration of active substance in the body necessary to achieve a therapeutic effect is maintained for a long time without the need to re-administer the drug at frequent intervals. In addition, administration of the active substance at prolonged intervals significantly contributes to the comfort of the patient. Particular preference is given to preparing pharmaceutical compositions which can be used therapeutically by one daily administration (single dose). The use of the drug once daily has the advantage that the patient can be relatively quickly accustomed to taking the drug regularly at certain times of the day.

For use as a medicament administered once daily, the active substance to be administered must meet certain requirements. First, the initiation of the desired activity should be made relatively quickly after administration of the drug, and ideally should have the same constant effect as possible over a very long time thereafter. In contrast, the duration of activity of the drug should not substantially exceed about 1 day. Ideally, the active substance has an activity profile that allows the preparation of a drug for once-daily administration containing a therapeutically effective amount of the active substance to be carefully controlled.

It has been found that the benzylic acid esters of scopine, trophenol and tropin described in WO 92/16528 do not meet these stringent requirements. Due to their very long-term activity substantially above the above-mentioned about 1 day, they cannot be used therapeutically for administration in one dose per day.

Accordingly, it is an object of the present invention to provide novel anticholinergic agents which allow the preparation of drugs for once-daily administration due to their activity profile. It is a further object of the present invention to prepare compounds characterized by a relatively rapid onset of activity. The invention also aims to provide compounds which have as constant activity as possible over a prolonged period of time after the rapid onset of activity. It is a further object of the present invention to provide compounds wherein the duration of activity does not substantially exceed about 1 day in a therapeutically effective amount. Finally, the present invention describes the provision of compounds having an activity profile that ensures good control of the therapeutic effect (ie, the total therapeutic effect not including the side effects caused by the accumulation of substances in the body).

Surprisingly, it has been found that the above objects are achieved by a compound of formula (I).

Formula 1

In the above formula,

,

및

중에서 선택되는 이중 결합된 그룹이고,A is

,

And

Double-bonded group selected from

X ^- is an anion with a single negative charge,

R ¹ and R ² are C ₁ -C ₄ -alkyl which may be optionally substituted by hydroxy or halogen,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and may be hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, hydroxy, CF ₃ , CN, NO ₂ or halogen Is,

R ⁷ is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ -alkylene-halogen, halogen-C ₁ -C ₄ -alkyloxy, C ₁ -C _4- Alkylene-OH, CF ₃ , -C ₁ -C ₄ -alkylene-C ₁ -C ₄ -alkyloxy, -O-COC ₁ -C ₄ -alkyl, -O-COC ₁ -C ₄ -alkyl-halogen , -O-COCF ₃ or halogen,

일 경우에, A

If is,

R ¹ and R ² are methyl,

R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen,

R ⁷ may also not be hydrogen.

Preferred compounds of formula (I)

,

및

중에서 선택되는 이중 결합된 그룹이고,A

,

And

Double-bonded group selected from

X ⁻ is an anion with a single negative charge selected from chloride, bromide, methylsulfate, 4-toluenesulfonate and methanesulfonate, preferably bromide,

R ¹ and R ² may be the same or different and are a group selected from methyl, ethyl, n-propyl and isopropyl, preferably unsubstituted methyl, which may be optionally substituted by hydroxy or fluorine,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ ,

R ⁷ is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F,- CH ₂ -OH, -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O- COMe, -O-COEt, -O-COCF ₃ , -O-COCF ₃ , fluorine, chlorine or bromine.

,

및

중에서 선택되는 이중 결합된 그룹이고,A

,

And

Double-bonded group selected from

X ⁻ is an anion with a single negative charge selected from chloride, bromide and methanesulfonate, preferably bromide,

R ¹ and R ² may be the same or different and are a group selected from methyl and ethyl, preferably unsubstituted methyl, which may be optionally substituted by hydroxy or fluorine,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine,

Particular preference is given to compounds of the formula 1 in which R ⁷ is hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF ₃ or fluorine.

Preferred compounds of formula 1 according to the invention

,

및

중에서 선택되는 이중 결합된 그룹이고,A

,

And

Double-bonded group selected from

X ^- is bromide,

R ¹ and R ² may be the same or different and are a group selected from methyl and ethyl, preferably methyl,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, methyloxy, chlorine or fluorine,

R ⁷ is hydrogen, methyl or fluorine.

및

중에서 선택되는 이중 결합된 그룹이고,A

And

Double-bonded group selected from

X ^- is bromide,

R ¹ and R ² may be the same or different and are methyl or ethyl, preferably methyl,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen or fluorine, preferably hydrogen,

Of particular importance in accordance with the invention are compounds of formula 1, wherein R ⁷ is hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.

The present invention optionally relates to compounds of formula 1 in the form of individual optical isomers, mixtures of individual enantiomers or racemates.

In the compound of formula 1, groups R ³ , R ⁴ , R ⁵ and R ⁶ may be present in the ortho, meta or para position for bonding to the "-CR ⁷ " group, respectively, if they are not hydrogen. When none of the groups R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, R ³ and R ⁵ are preferably linked in the para position and R ⁴ and R ⁶ are preferably the ortho or meta position, most preferably Is linked at the meta position. When one of the groups R ³ and R ⁴ and one of the groups R ⁵ and R ⁶ are hydrogen, in each case the remaining groups are preferably linked in the meta or para position, most preferably in the para position. When none of the groups R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, particular preference is given to compounds according to the invention in which the groups R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning.

Of particular importance in accordance with the invention are compounds of formula (1) in which the ester-substituent on the nitrogen-bicyclic group is present in the α-configuration. Such compounds correspond to formula 1-α

According to the invention, the following compounds are of particular importance:

-Trophenol 2,2-diphenylpropionate-methobromide;

-Scopin 2,2-diphenylpropionate-methobromide;

-Scopin 2-fluoro-2,2-diphenylacetate-methobromide;

-Trophenol 2-Fluoro-2,2-diphenylacetate-methobromide.

Unless stated otherwise, alkyl groups are straight or branched chain alkyl groups having 1 to 4 carbon atoms. Examples are methyl, ethyl, propyl or butyl. In some cases, the abbreviation Me, Et, Prop or Bu will be used to mean the group methyl, ethyl, propyl or butyl. Unless stated otherwise, the definitions of propyl and butyl include all possible isomeric forms of the group. Thus, for example, propyl includes n-propyl and isopropyl, butyl means isobutyl, secondary-butyl and tert-butyl and the like.

Unless stated otherwise, alkylene groups are double bond side chain and straight chain alkyl bridges having 1 to 4 carbon atoms. Examples are methylene, ethylene, propylene or butylene.

Unless stated otherwise, alkylene-halogen groups are mono-, di-, or tri-substituted, preferably mono-substituted, double-bonded, branched and straight chain alkyl bridges of 1 to 4 carbon atoms by halogen. Thus, unless stated otherwise, alkylene-OH groups are mono-, di-, or tri-substituted, preferably mono-substituted, double-bonded, branched and straight chain alkyl bridges of 1 to 4 carbon atoms by hydroxy.

Unless stated otherwise, the term alkyloxy group refers to branched and straight chain alkyl groups having 1 to 4 carbon atoms linked via an oxygen atom. Examples thereof include methyloxy, ethyloxy, propyloxy or butyloxy. The abbreviations MeO-, EtO-, PropO- or BuO- are in some cases used to mean the group methyloxy, ethyloxy, propyloxy or butyloxy. Unless stated otherwise, the definitions of propyloxy and butyloxy include all possible isomeric forms of the group. Thus, for example, propyloxy includes n-propyloxy and isopropyloxy, butyloxy includes isobutyloxy, secondary-butyloxy, tert-butyloxy and the like. In some cases, the term alkoxy is used in place of the term alkyloxy within the scope of the present invention. Thus, the term methoxy, ethoxy, propoxy or butoxy may be used to mean the group methyloxy, ethyloxy, propyloxy or butyloxy.

Unless otherwise stated, the term alkylene-alkyloxy group means mono-, di-, or tri-substituted, preferably mono-substituted, double-bonded, branched and straight chain alkyl bridges of 1 to 4 carbon atoms by alkyloxy groups. .

Unless stated otherwise, the term -O-CO-alkyl group refers to branched and straight chain alkyl groups having 1 to 4 carbon atoms, linked through ester groups. Alkyl groups are directly linked to the carbonyl carbon of the ester group. The term -O-CO-alkyl-halogen group is to be understood in the same way. Group-O-CO-CF ₃ means trifluoroacetate.

Halogen within the scope of the present invention means fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are preferred halogens. Group CO means carbonyl group.

The compounds according to the invention can be prepared in part, analogously to methods already known from the prior art, as described below (Scheme 1). Carboxylic acid derivatives of formula 3 are known in the art or can be obtained using synthetic methods known in the art. If only suitably substituted carboxylic acids are known in the art, the compounds of formula 3 are suitably substituted by acid-catalyzed or base-catalyzed esterification with the corresponding alcohols or halogenation with the corresponding halogenation reagents. It can be obtained directly from the carboxylic acid.

Starting from the compound of formula (2), the ester of formula (4) can be obtained by reacting a carboxylic acid derivative of formula (3) wherein R can be, for example, a chlorine or C ₁ -C ₄ -alkoxy group. When R is C ₁ -C ₄ -alkoxy, the reaction is, for example, at elevated temperature, preferably at about 50 to 150 ° C., most preferably at 90 to 100 ° C., at low pressure, preferably at most 500 mbar, most preferably Preferably in molten sodium at 75 mbar or lower. Alternatively, instead of the derivative (3) in which R is C ₁ -C ₄ -alkyloxy, the corresponding acid chloride (R is Cl) can be used.

The compound of formula 4 thus obtained can be converted to the target compound of formula 1 by reacting with a compound of formula R ² -X wherein R ² and X can be as defined above. This synthetic step may be carried out analogously to the synthetic examples described in WO 92/16528.

As an alternative to the method described in Scheme 1 for synthesizing the compound of formula 4, the derivative (4) in which the nitrogen bicyclic group is a scopine derivative, and the compound of formula 4 in which the nitrogen-bicyclic group is a trophenyl group It can be obtained by oxidation (epoxidation). This can be done according to the invention as follows. Compound (4) wherein A is -CH = CH- is selected from polar organic solvents, preferably N-methyl-2-pyrrolidine (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide. It is suspended in a solvent and then heated to a temperature of about 30 to 90 캜, preferably 40 to 70 캜. A suitable oxidant is then added and the mixture is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. Preferred oxidants are vanadium pentoxide mixed with H ₂ O ₂ , most preferably H ₂ O ₂ -urea complexes combined with vanadium pentoxide. The mixture is worked up in the usual way. The product can be purified by crystallization or chromatography, depending on its tendency to crystallize.

In addition, compounds of formula 4 wherein R ⁷ is halogen can be obtained using the method shown in Scheme 2 below.

To this end, the benzyl acid ester of formula 5 is converted to compound 4, wherein R ⁷ is halogen using a suitable halogenation reagent. The halogenation reaction to be carried out according to Scheme 2 is already well known in the art.

Benzylic acid esters of formula 5 can be obtained according to or similarly known in the art (see WO 92/16528).

 As shown in Scheme 1, the intermediate product of formula 4 is of critical importance. Thus, in another aspect, the present invention relates to an intermediate of formula (4).

In the above formula,

,

및

중에서 선택되는 이중 결합된 그룹이고,A is

,

And

Double-bonded group selected from

R ¹ is C ₁ -C ₄ -alkyl, which may be optionally substituted by hydroxy or halogen,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and may be hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, hydroxy, CF ₃ , CN, NO ₂ or halogen ego,

R ⁷ is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ -alkylene-halogen, halogen-C ₁ -C ₄ -alkyloxy, C ₁ -C _4- Alkylene-OH, CF ₃ , -C ₁ -C ₄ -alkylene-C ₁ -C ₄ -alkyloxy, -O-COC ₁ -C ₄ -alkyl, -O-COC ₁ -C ₄ -alkyl-halogen , -O-COCF ₃ or halogen,

일 경우,A

If,

R ¹ is methyl,

R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen,

R ⁷ may be n-propyl.

,

및

중에서 선택되는 이중 결합된 그룹이고,A

,

And

Double-bonded group selected from

R ¹ may be the same or different and is a group selected from methyl, ethyl, n-propyl and isopropyl, preferably unsubstituted methyl, which may be optionally substituted by hydroxy or fluorine,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ ,

R ⁷ is hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F,- CH ₂ -OH, -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O- Preference is given to compounds of the formula (1) which are COMe, -O-COEt, -O-COCF ₃ , -O-COCF ₃ , fluorine, chlorine or bromine.

,

및

중에서 선택되는 이중 결합된 그룹이고,A

,

And

Double-bonded group selected from

R ¹ may be the same or different and is a group selected from methyl and ethyl, preferably unsubstituted methyl, which may be optionally substituted by hydroxy or fluorine,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine,

Particular preference is given to compounds of the formula 1 in which R ⁷ is hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF ₃ or fluorine.

Preferred compounds of formula 1 according to the invention

,

및

중에서 선택되는 이중 결합된 그룹이고,A

,

And

Double-bonded group selected from

R ¹ may be the same or different and is a group selected from methyl and ethyl, preferably methyl,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, methyloxy, chlorine or fluorine,

R ⁷ is hydrogen, methyl or fluorine.

및

중에서 선택되는 이중 결합된 그룹이고,A

And

Double-bonded group selected from

R ¹ may be the same or different and is methyl or ethyl, preferably methyl,

R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen or fluorine, preferably hydrogen,

Of particular importance according to the invention are compounds in which R ⁷ is hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.

As in the compound of formula 1, in the intermediate of formula 4 the groups R ³ , R ⁴ , R ⁵ and R ⁶ are ortho, meta or para positions for binding to the "-CR ⁷ " group, respectively, if they are not hydrogen; May exist in When none of the groups R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, R ³ and R ⁵ are preferably linked in the para position and R ⁴ and R ⁶ are preferably the ortho or meta position, most preferably Is linked at the meta position. When one of the groups R ³ and R ⁴ and one of the groups R ⁵ and R ⁶ are hydrogen, in each case the remaining groups are preferably linked in the meta or para position, most preferably in the para position. When none of the groups R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, particular preference is given to compounds according to the invention in which the groups R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning.

The invention is further illustrated by the synthetic examples described below. However, these examples are merely method embodiments as an explanation of the present invention, not limited to the actual contents described by the examples.

Example 1 Scopin-2,2-Diphenylpropionate-Methobromide:

1.1: 2,2-diphenylpropionic acid chloride (3a):

52.08 g (0.33 mol) of oxalyl chloride are slowly added dropwise to a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 ml of dichloromethane and 4 drops of dimethylformamide at 20 ° C. The mixture is stirred at 20 ° C. for 1 hour and at 50 ° C. for 0.5 hour. The solvent is distilled off and the remaining residue is used without any further purification in the next step.

1.2: scopine 2,2-diphenylpropionate (4a)

The residue obtained in step 1.1 is dissolved in 100 ml of dichloromethane and a solution of 51.45 g (0.33 mol) of scopine in 200 ml of dichloromethane is added dropwise at 40 ° C. The resulting suspension is stirred at 40 ° C. for 24 hours, then the precipitate formed is filtered off with suction and the filtrate is first acidically extracted with water followed by aqueous hydrochloric acid. The combined aqueous phases are made alkaline with aqueous sodium carbonate solution and extracted with dichloromethane, the organic phases are dried over Na ₂ SO ₄ and then evaporated to dryness, and the hydrochloride is precipitated from the residue. The product is purified by recrystallization from acetonitrile.

Yield: 20.85 g (= 47% of theory)

TLC: Rf value: 0.24 (eluent: secondary-butanol / formic acid / water 75:15:10);

Melting point: 203 to 204 캜.

1.3: scopine 2,2-diphenylpropionate-methobromide:

11.98 g (0.033 mol) of compound (4a), 70 ml of dichloromethane and 20.16 g (0.1 mol) of 46.92% bromomethane in acetonitrile are combined at 20 ° C. and left to stand for 3 days. The solution is evaporated to dryness and the residue is recrystallized from isopropanol.

Yield: 11.34 g (= 75% of theory); Melting point: 208 to 209 ° C.

C ₂₄ H ₂₈ NO ₃ xBr (458.4);

Elemental Analysis: Calculation: C (62.89) H (6.16) N (3.06)

Found: C (62.85) H (6.12), N (3.07).

Example 2: Scopin 2-Fluoro-2,2-diphenylacetate-methobromide:

2.1 scopine benzylate (5a)

 The preparation of scopin benzylates is known in the art. This is described in WO 92/16528.

2.2: scopine 2-fluoro-2,2-diphenylacetate (4b)

2.66 g (0.02 mol) of dimethylaminosulfur trifluoride are cooled to 0 ° C. in 10 ml of dichloromethane and 5.48 g (0.015 mol) of scopine benzylate (5a) in 100 ml of dichloromethane are added dropwise. The mixture is then stirred for an additional 30 minutes at 0 ° C. and for 30 minutes at 20 ° C. Cool the solution, combine with water, add NaHCO ₃ (until pH 7-8) and separate organic phase. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water and dried over Na ₂ SO ₄ and then evaporated to dryness.

Hydrochloride is precipitated from the residue and recrystallized from acetonitrile.

Yield: 6.90 g (= 85% of theory)                 

Melting point: 227-230 degreeC.

2.3: scopine 2-fluoro-2,2-diphenylacetate-methobromide:

2.88 g (0.0078 mol) of free base of scopin benzylate are reacted analogously to the method of step 1.3. The product is purified by recrystallization from isopropanol. Yield: 2.62 g (= 73% of theory).

TLC: Rf value: 0.31 (eluent as in step 1.2); Melting point: 130-134 ° C.

Example 3: Trophenol 2,2-diphenylpropionate-methobromide:

3.1 .: Methyl 2,2-diphenylpropionate (3b):

37.60 g (0.247 mol) of DBU are added dropwise to a suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 ml of acetonitrile at 20 ° C. 70.10 g (0.494 mol) of methyl iodide is added dropwise to the resulting solution within 30 minutes. The mixture is then stirred at 20 ° C. overnight. The solvent is evaporated and the residue is extracted with diethylether / water, the organic phase is washed with water, dried over Na ₂ SO ₄ and evaporated to dryness. Yield: viscous residue 32 48.29 g (= 89% of theory).

3.2: Trophenol 2,2-diphenylpropionate (4c):

4.80 g (0.02 mol) of methyl 2,2-diphenylpropionate (3b), 2.78 g (0.02 mol) of trophenol and 0.046 g of sodium are heated as a melt at 75 mbar for 4 hours in a boiling water bath with shaking every hour. . After cooling, the sodium residue is dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane / water. The organic phase is washed with water and dried over MgSO ₄ and then evaporated to dryness.

From the residue, compound 4c is precipitated as hydrochloride and it is recrystallized from acetone.

Yield: 5.13 g (= 67% of theory);

TLC: Rf value: 0.28 (eluent: secondary-butanol / formic acid / water 75:15:10);

Melting point: 134-135 degreeC.

3.3: Trophenol 2,2-diphenylpropionate-methobromide:

2.20 g (0.006 mol) of compound (4c) are reacted similarly to step 1.3 of Example 1. The crystals formed are suction filtered, washed with dichloromethane and dried and then recrystallized from methanol / diethyl ether.

Yield: 1.84 g (= 66% of theory);

TLC: Rf value: 0.11 (eluent as in step 1.2); Melting point: 222-223 degreeC.

C ₂₄ H ₂₈ NO ₂ xBr (442.4);

Elemental Analysis: Calculation: C (65,16) H (6.38) N (3.17)                 

           Found: C (65,45) H (6.29) N (3.16).

Example 4: Trophenol 2-Fluoro-2,2-bis (3,4-difluorophenyl) acetate-methobromide:

4.1 .: Ethyl 3,3 ', 4,4'-tetrafluorobenzylate (3c):

The Grignard reagent is prepared from 2.24 g (0.092 mol) of magnesium flakes, several granules of iodine and 17.80 g (0.092 mol) of 1-bromo-3,4-difluoro-benzene in 50 ml of THF at 50 ° C. After all the halides have been added, the mixture is stirred for additional time. The Grignard reagent thus obtained was added dropwise to 18.81 g (0.088 mol) of ethyl 3,4-difluorophenylglyoxylate in 80 ml of THF at 10 ° C to 15 ° C, and the resulting mixture was stirred at 5 ° C for 2 hours. do. The white suspension is poured into ice / sulfuric acid for workup and extracted with ethyl acetate and the organic phase washed with water and dried over MgSO ₄ and then evaporated to dryness. The crude product is purified by column chromatography (eluent: toluene).

Yield: 10.80 g of oil (= 38% of theory)                 

4.2 .: Trophenol 3,3'4,4'-tetrafluorobenzylate (5b):

75 mbar for 4 h in a boiling water bath, shaking 4.27 g (0.013 mol) of ethyl 3,3'4,4'-tetrafluorobenzylate (3c), 1.81 g (0.013 mol) of trophenol and 0.03 g of sodium every hour Heated as melt. After cooling, the sodium residue is dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane / water. The organic phase is washed with water and dried over MgSO ₄ and then evaporated to dryness. The remaining residue is mixed with diethyl ether / petroleum ether 1: 9, suction filtered and washed.

Yield: 2.50 g (= 46% of theory);

TLC: Rf value: 0.29 (eluent: secondary butanol / formic acid / water 75:15:10);

Melting point: 147 ° C to 148 ° C.

4.3: Trophenol 2-Fluoro-2,2-bis (3,4-difluorophenyl) acetate (4d):

2.66 g (0.012 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride were placed in 10 ml of dichloromethane, and within 20 minutes, 0.01 mol of compound (5b) in 65 ml of dichloromethane at 15 ° C. to 20 ° C. Add it down. The mixture is stirred at room temperature for 20 hours, cooled to 0 ° C. and carefully mixed with 80 ml of water with thorough stirring. The mixture is then carefully adjusted to pH 8 with aqueous NaHCO ₃ solution, the organic phase is separated, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water and dried over MgSO ₄ and then evaporated to dryness. . Hydrochloride is precipitated and recrystallized from acetonitrile / diethyl ether. Yield: 2.60 g of white crystals (= 57% of theory); Melting point: 233 ° C.

4.4: Trophenol 2-fluoro-2,2-bis (3,4-difluorophenyl) acetate-methobromide :

2.20 g (0.0052 mol) of compound (4d) are reacted similarly to step 1.3 of Example 1. The crystals formed are suction filtered, the dichloromethane is washed and dried and then recrystallized from methanol / diethyl ether.

Yield: 1.95 g (= 72% of theory);

TLC: Rf value: 0.17 (eluent: n-butanol / water / formic acid (concentrated) / acetone / dichloromethane 36: 15: 15: 15: 5); Melting point: 247 ° C.

C ₂₃ H ₂₁ F ₅ NO ₂ xBr (518.3);

Elemental Analysis: Calculation: C (53.30) H (4.08) N (2.70)

Found: C (53.22) H (4.19) N (2.69).

Example 5: Scopin 2,2-diphenylpropionate-ethylbromide

1.81 g (0.005 mol) of compound (4a), 35 ml of acetonitrile and 1.64 g (0.015 mol) of ethyl bromide are combined at 20 ° C. and left to stand for 3 days. The solution is evaporated to dryness and the residue is recrystallized from ethanol.

Yield: 1.38 g (= 58% of theory); Melting point: 208 to 209 ° C.

TLC: Rf value: 0.33 (eluent as in step 1.2); Melting point: 210 to 211 ° C.

C ₂₅ H ₃ ONO ₃ xBr (472.42);

Elemental Analysis: Calculation: C (63.56) H (6.40) N (2.96)

Found: C (63.49) H (6.24) N (2.88).

Example 6: Scopin 2-fluoro-2,2-bis (3,4-difluorophenyl) acetate-methobromide :

6.1. :  Scopin 3,3'4,4'-tetrafluorobenzylate (5c):

3.61 g (0.011 mol) of 3,3'4,4'-tetrafluorobenzylate (3c), 1.71 g (0.011 mol) of scopine and 0.03 g of sodium, shaking at 75 mbar for 4 hours in a boiling water bath. Heat as a melt. After cooling, the sodium residue is dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane / water. The organic phase is washed with water and dried over MgSO ₄ and then evaporated to dryness. The remaining residue is mixed with diethyl ether / petroleum ether 1: 9, suction filtered and washed. Yield: 1.75 g (= 36% of theory); Melting point: 178 to 179 ° C.

6.2: scopin 2-fluoro-2,2-bis (3,4-difluorophenyl) acetate (4e):

0.6 ml (0.0033 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride are reacted with 1.2 g (0.0028 mol) of compound (5c) similar to step 4.3 of Example 4.

Yield: 1.15 g of colorless oil (= 95% of theory)

6.3:Scopin 2-fluoro-2,2-bis (3,4-difluorophenyl) acetate-methobromide :

1.15 g (0.0026 mol) of compound (4e) and 1.5 g (0.0079 mol) of 50% methyl bromide solution are reacted similarly to step 1.3 of Example 1. The crystals formed are suction filtered, washed with dichloromethane and dried and then recrystallized from acetone.

Yield: 0.88 g (= 63% of theory)

TLC: Rf value: 0.27 (eluent: n-butanol / water / formic acid (concentrated) / acetone / dichloromethane 36: 15: 15: 15: 5); Melting point: 212 ° C.

C ₂₃ H ₂₁ F ₅ NO ₃ xBr (535.33);

Example 7: Trophenol 2-Fluoro-2,2-bis (4-fluorophenyl) acetate-method romanide :

7.1 .: Methyl 4,4'-difluorobenzylate (3d) :.

7.1.1 .: 4,4'-difluorobenzyl acid:

At about 100 ° C. 24.62 g (0.1 mol) of 4,4′-difluorobenzyl in 250 mL of dioxane is added dropwise to a solution of 49.99 g (1.25 mol) of NaOH flakes in 300 mL of water and stirred for 2 hours. Dioxane is distilled in large quantities and the remaining aqueous solution is extracted with dichloromethane. When the aqueous solution is acidified with sulfuric acid, a precipitate is formed which is suction filtered, washed and dried. The filtrate is extracted with dichloromethane and the organic phase is dried over Na ₂ SO _{4 and} then evaporated to dryness.

Yield: 25.01 g (= 95% of theory); Melting Point: 133-136 ° C

7.1.2 .: Methyl 4,4'-difluorobenzylate:

25.0 g (0.095 mol) of 4,4'-difluorobenzyl acid are added to 200 ml of freshly prepared sodium ethoxide and ethanol containing 2.17 g (0.095 mol) of sodium at 20 ° C and stirred for 3 hours. The solution is evaporated to dryness, the residue is dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide is added dropwise at 20 ° C. and the mixture is stirred for 24 hours. It is worked up and purified similarly to compound (3b). Yield: 11 21.06 g (= 80% of theory).

7.2 .: Trophenol 4,4'-difluorobenzylate (5d):

11.13 g (0.04 mol) of methyl 4,4′-difluorobenzylate (3d) and 5.57 g (0.04 mol) of trophenol are reacted with 0.09 g of sodium, similar to step 3.2 of Example 3. The product is recrystallized from acetonitrile.

Yield: 10.43 g (= 62% of theory);

Melting point: 233 to 235 ° C.

7.3: Trophenol 2-fluoro-2,2-bis (4-fluorophenyl) -acetate (4f):

2.94 g (0.013 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride are reacted with 3.85 g (0.01 mol) of compound (5d) in 100 ml of dichloromethane similarly to step 4.3 of Example 4. . The product is recrystallized from acetonitrile in its hydrochloride form.

Yield: 2.93 g (= 69% of theory)

7.4:Trophenol 2-fluoro-2,2-bis (4-fluorophenyl) -acetate-methobromide :

2.6 g (0.0067 mol) of compound (4f) and 1.9 g (0.0079 mol) of 50% methyl bromide solution are reacted similarly to step 1.3 of Example 1. The crystals formed are suction filtered, washed with dichloromethane and dried and then recrystallized from methanol / diethyl ether.

Yield: 2.82 g of white crystals (= 87% of theory)

TLC: Rf value: 0.55 (eluent: follow step 1.2 of Example 1);

Melting point: 230-231 ° C.

C ₂₃ H ₂₃ F ₃ NO ₂ xBr (482.34);

Elemental Analysis: Calculation: C (57.27) H (4.81) N (2.90)

Found: C (57.15) H (4.84) N (2.96).

Example 8: Scopin 2-fluoro-2,2-bis (4-fluorophenyl) acetate-methobromide:

8.1: scopine 4,4'-difluorobenzylate (5e):

Trophenol 4.22 g (0.01 mol) of 4,4'-difluorobenzylate (5d) is suspended in 80 ml of DMF. At an internal temperature of about 40 ° C., 0.2 g (0.0011 mol) of vanadium oxide (V) is added together with a solution of 2.57 g (0.0273 mol) of H ₂ O ₂ -urea in 20 ml of water, and the resulting mixture is stirred at 60 ° C. Stir for 4.5 hours. After cooling to 20 ° C., the formed precipitate is suction filtered and the filtrate is adjusted to pH 3 with 4N hydrochloric acid and combined with Na ₂ S ₂ O ₅ dissolved in water. The green solution obtained is evaporated to dryness and the residue is extracted with dichloromethane / water. The acidic aqueous phase is made basic with Na ₂ CO ₃ , extracted with dichloromethane and the organic phase is dried over Na ₂ SO ₄ and concentrated.

0.5 ml of acetylchloride is then added at about 15 ° C. and stirred for 1.5 hours. After extraction with 0.1N hydrochloric acid, the aqueous phase is made basic, extracted with dichloromethane, the organic phase is dried over Na ₂ SO _{4 and} then evaporated to dryness. Hydrochloride is precipitated from the residue and recrystallized from methanol / diethyl ether.

Yield: 3.61 g of white crystals (= 78% of theory);

Melting point: 243 to 244 ° C.

8.2: scopine 2-fluoro-2,2-bis (4-fluorophenyl) -acetate (4 g):

1.48 g (0.0067 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride are reacted with 2.0 g (0.005 mol) of 5e in 80 ml of dichloromethane similarly to step 4.3 of Example 3. The product is recrystallized from ethanol in its hydrochloride form.

Yield: 2.07 g (= 94% of theory); Melting point: 238 to 239 ° C.

8.3: scopine 2-fluoro-2,2-bis (4-fluorophenyl) -acetate-methobromide:                 

1.6 g (0.004 mol) of Compound (4 g) and 1.14 g (0.0079 mol) of 50% methyl bromide solution are reacted similarly to Step 1.3 of Example 1. The crystals formed are suction filtered, washed with dichloromethane and dried and then recrystallized from acetonitrile.

Yield: 1.65 g of white crystals (= 61% of theory)

TLC: Rf value: 0.25 (eluent: follow step 1.2 of Example 1);

Melting point: 213 to 214 ° C.

C ₂₃ H ₂₃ F ₃ NO ₃ xBr (498.34);

Elemental Analysis: Calculation: C (55.43) H (4.65) N (2.81)

Found: C (54.46) H (4.67) N (2.80).

Example 9: Trophenol 2-Fluoro-2,2-diphenylacetate-methobromide:

9.1 .: Trophenol benzylate (5f):.

Trophenol benzylates and methods for their preparation are known from WO 92/16528.

9.2: trophenol 2-fluoro-2,2-diphenylacetate (4h):

15.86 ml (0.086 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride are reacted with 25 g (0.072 mol) of compound (5f) in 480 ml of chloroform similarly to step 4.3 of Example 4. The product is recrystallized from acetone in its hydrochloride form. Yield: 18.6 g white crystals (= 67% of theory); Melting point: 181 to 182 ° C.

9.3: Trophenol 2-fluoro-2,2-diphenyl-acetate-methobromide:

11.12 g (0.032 mol) of Compound (4b) and 18.23 g (0.096 mol) of 50% methyl bromide solution are reacted similarly to Step 1.3 of Example 1. The crystals formed are recrystallized from acetonitrile.

Yield: 11.91 g of white crystals (= 83% of theory);

TLC: Rf value: 0.4 (eluent: follow step 4.4 of Example 4);

Melting point: 238 to 239 ° C .;

C ₂₃ H ₂₅ FNO ₂ xBr (446.36);

Elemental Analysis: Calculation: C (61.89) H (5.65) N (3.14)

Found: C (62.04) H (5.62) N (3.17).

Example 10:Trophenol 2-fluoro-2,2- (3-chlorophenyl) acetate-methobromide :

10.1 .: Methyl 3,3'-dichlorobenzylate (3e):

10.1.1 .: 3,3'-dichlorobenzyl:

100 ml of ethanol are used at room temperature and 50.0 g (0.356 mol) of 3-chlorobenzaldehyde and 4.54 g (0.018 mol) of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide are added. Subsequently, 10.7 g (0.11 mol) of triethylamine is added dropwise. The mixture is refluxed for 3 hours and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water, sodium pyrosulfite and Na ₂ CO ₃ solution in water. After drying over MgSO ₄ , it is evaporated to dryness. The product obtained is recrystallized from isopropanol and petroleum ether.

Yield: 13.2 g of white crystals (= 13% of theory); Melting point: 69-70 ° C.

13.0 g of acyloin thus obtained is dissolved in 460 ml of acetonitrile at room temperature, 0.0867 g of vanadium oxytrichloride (V) is added, and oxygen is introduced through the tube. After 1.5 hours, the solution is evaporated to dryness, extracted with ethyl acetate and water and Na ₂ CO ₃ solution, dried over MgSO ₄ and then evaporated to dryness. The remaining residue is stirred with petroleum ether / ethyl acetate 95: 5.

Yield: 12.59 g of yellow crystals (= 97% of theory); Melting point: 116-117 degreeC.

10.1.2 .: 3,3'-dichlorobenzyl acid:

51.45 g (1.286 mol) of sodium hydroxide in 1000 ml of water are placed in a boiling water bath with thorough stirring, 28.5 g (0.102 mol) of 3,3'-dichlorobenzyl in 700 ml of dioxane are added dropwise, and then for an additional hour Stir. After cooling, the dioxane is evaporated and the residue is diluted with water and extracted with diethyl ether. The organic phase is acidified, extracted with dichloromethane and dried over MgSO ₄ and then evaporated to dryness.

Yield: 32.7 g (= 71% of theory).

10.1.3 .: Methyl 3,3'-dichlorobenzylate:

From 100 mL of ethanol and 1.97 g (0.0855 mol) of sodium, a sodium ethoxide solution is prepared, to which 26.6 g (0.0855 mol) of 3,3'-dichlorobenzyl acid in 50 ml of ethanol is added dropwise. The mixture is then stirred for 4 hours at room temperature. After distilling off the solvent, the residue was dissolved in 150 mL of DMF, 24.27 g (0.171 mol) of methyl iodide was added dropwise, followed by stirring for an additional 24 hours. While cooling with ice, 300 ml of water and 200 ml of diethyl ether were added dropwise and the phases were separated, the aqueous phase was extracted with diethyl ether, the organic phase was washed with Na ₂ CO ₃ solution and shaken with water until neutral. Let's do it. After drying over Na ₂ SO ₄ , the mixture is evaporated to dryness. Yield: 22.91 g of yellow oil (= 82% of theory).

10.2 .: Trophenol 3,3'-dichlorobenzylate (5 g):

22.9 g (0.074 mol) of methyl 3,3'-dichlorobenzylate (3e), 15.37 g (0.11 mol) of triphenol and 0.17 g of sodium are heated as a melt at 75 mbar for 4 hours in a boiling water bath with occasional shaking. After cooling, the sodium residue is dissolved with acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane / water. The organic phase is washed with water and dried over MgSO ₄ and then evaporated to dryness. The product is recrystallized from acetonitrile in its hydrochloride form. Yield: 16.83 g of white crystals (= 50% of theory); Melting point: 184 to 185 ° C.

10.3: trophenol 2-fluoro-2,2-bis (3-chlorophenyl) acetate (4i):

1.48 g (0.0067 mol) of bis- (2-methoxyethyl) -aminosulfur trifluoride was used in 10 mL of dichloromethane, and the compound (5 g) 2.09 in 65 mL of dichloromethane at 15 ° C. to 20 ° C. within 20 minutes. g solution is added dropwise. The mixture is stirred at room temperature for 20 hours, cooled to 0 ° C. and carefully combined with 80 ml of water with thorough stirring. The mixture is then carefully adjusted to pH 8 using aqueous NaHCO ₃ solution, the organic phase is separated and the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water and dried over MgSO ₄ and then evaporated to dryness. Hydrochloride is precipitated and recrystallized from acetonitrile / diethyl ether. Yield: 1.20 g of white crystals (= 53% of theory); Melting point: 136 to 137 ° C.

10.4: trophenol 2-fluoro-2,2-bis (3-chlorophenyl) acetate-methobromide:

1.0 g (0.002 mol) of compound (4h) is reacted similarly to step 1.3 of Example 1. The crystals formed are suction filtered, washed with dichloromethane and dried and then recrystallized from methanol / diethyl ether. Yield: 0.82 g of white crystals (= 80% of theory); TLC: Rf value: 0.14 (eluent: n-butanol / water / formic acid (concentrated) / acetone / dichloromethane 36: 15: 15: 15: 5); Melting point: 180-181 ° C. C ₂₃ H ₂₃ Cl ₂ FNO ₂ xBr (515.25).

As identified, the compound of formula 1 is characterized by its versatility in its therapeutic use. Particular mention may be made of the use of the compounds of the formula (1) according to the invention, preferably on the basis of their pharmaceutical activity as anticholinergic agents. This includes, for example, treating asthma or COPD (chronic obstructive pulmonary disease). As identified, the compound of formula 1 can also be used to treat vagally induced sinus bradycardia and heart rate disorders. In general, the compounds according to the invention can also be used therapeutically advantageously, for example, in the treatment of spasms of the gastrointestinal tract. In addition, the compounds of the present invention can be used, for example, in the treatment of spasms of the urinary tract and menstrual disorders. Of the abovementioned ranges, the treatment of asthma and COPD with the compound of formula 1 according to the invention is of particular importance.

The compound of formula 1 can be used alone or in combination with other active substances of formula 1 according to the invention.

The compound of formula 1 may optionally be combined with other pharmacologically active substances. Such pharmacologically active substances include in particular betamimetics, antiallergic agents, PAF-antagonists, leukotriene-antagonists and corticosteroids and combinations of these active substances.

Examples of beta mimetics that can be used with the compound of formula 1 according to the invention include optionally racemates, enantiomers, diastereomers, as well as optionally pharmaceutically acceptable acid addition salts and hydrate forms of bambuterol, Bitoleol, Carbuterol, Clenbuterol, Phenoterol, Formoterol, Hexoprelinin, Ibuterol, Pyrbuterol, Procaterol, Leproterol, Salmeterol, Sulfonterol, Terbutalin, Tolubu Terrol, 4-hydroxy-7- [2-{[2-{[3- (2-phenylethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1 -(2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol , 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl- 2-propylamino] ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino ]ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2- Propylamino] ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4 -Triazol-3-yl] -2-methyl-2-butylamino} ethanol , 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro -5-trifluoromethylphenyl) -2-tert-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tertiary-Butylamino) ethanol. As beta mimetics, optionally racemates, enantiomers, diastereomers, as well as phentolol, formoterol, salmeterol, 1- [3- ( 4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl- 2-propylamino] ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino ]ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2- Propylamino] ethanol , 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,2,4 -Triazol-3-yl] -2-methyl-2-butylamino} ethanol  Particular preference is given to using in combination with the compounds of the formula (1) according to the invention an active substance of this kind selected from among them. Of the beta mimetics mentioned above, the compounds formoterol and salmeterol, in the form of pharmaceutically acceptable acid addition salts and hydrates, as well as racemates, enantiomers, diastereomers, are of particular interest.

Acid addition salts of beta mimetics selected from hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and guafoate are preferred according to the invention. In the case of salmeterol, salts selected from hydrochloride, sulfate and ginafoate are particularly preferred, and more particularly sulfate and ginafoate are preferred. Salmeterol x 1/2 H ₂ SO ₄ and salmeterol ginafoate are very important according to the invention. In the case of formoterol, salts selected from hydrochloride, sulfate and fumarate are particularly preferred, more particularly hydrochloride and fumarate. Formoterol fumarate is very important according to the invention.

In the scope of the present invention, corticosteroids which can optionally be used with the compound of formula 1 are flunisoleide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, loflefonide, GW 215864, KSR 592, ST-126, and dexamethasone. Preferred corticosteroids within the scope of the present invention are corticosteroids selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone, and budesonide, pullulica Of particular importance are hands, mometasone and ciclesonide, in particular budesonide and fluticasone. The term steroid agent may be used alone in place of the term corticosteroid agent within the scope of this patent application. All meanings for steroids within the scope of the present invention also include meanings for salts or derivatives that may be formed from steroids. Examples of possible salts or derivatives include sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Corticosteroids may optionally be present in their hydrate form.

Within the scope of the present invention, the term dopamine agonist, which may optionally be used in combination with a compound of formula (1), is bromocriptine, cabergoline, alpha-dihydroergocriptine, risulide, pergolide, pramipexole, It means a compound selected from Roxindole, Ropinillol, Talipexole, Terguride and Biozan. Within the scope of the present invention it is preferred to use dopamine agonists selected from pramipexole, delipexole and biozan as combination partners with formula (1), pramipexole being particularly important. Within the scope of the present invention, the meanings for the above-mentioned dopamine agonists also include the meanings for all pharmaceutically acceptable acid addition salts and hydrates thereof that may be present. Physiologically acceptable acid addition salts thereof that may be formed by the above-mentioned dopamine agonists include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid It means a pharmaceutically acceptable salt selected from salts of tartaric acid and maleic acid.

Examples of anti-allergic agents which may be used according to the invention as a combination with a compound of formula (I) include efinastin, cetirizine, azelastine, fexofenadine, levocavastin, loratadine, mizolastine, ketotifen, emeda Stine, Dimethindene, Clemastine, Bamipine, Hixchloropheniramine, Peniamine, Doxylamine, Chlorophenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine, Evastin, Desloratidine and Meclizin Included. Preferred anti-allergic agents that can be used in combination with the compound of formula 1 according to the invention within the scope of the invention are epinastine, cetirizine, azelastine, fexofenadine, levocastin, loratadine, evastin, deslorati Dine and mizolastine, efinastin and desloratidine are particularly preferred. In the scope of the present invention, all meanings for the above-mentioned antiallergic agents also include the meanings for all pharmaceutically acceptable acid addition salts thereof which may be present.

Examples of PAF antagonists that can be used with the compounds of Formula 1 according to the present invention are as follows:

4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanon-1-yl] -6H-

Thieno- [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine,

6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8-[(4-morpholinyl) carbonyl] -4H, 7H-cyclopenta- [4,5] thieno- [ 3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine.

When the compounds of the formula (1) are used in combination with other active substances, combinations with steroids or beta mimetics are particularly preferred in all categories of the aforementioned compounds. Of particular importance are beta mimetics, especially combinations with beta mimetics with long lasting activity. Particular preference is given to combinations of the compounds of formula (1) according to the invention with salmeterol or formoterol, most preferably with formoterol.

Formulations suitable for administering the compound of formula 1 include tablets, capsules, suppositories, solutions, and the like. Particularly important according to the invention is the administration of the compounds according to the invention by inhalation, especially when treating asthma or COPD. The pharmaceutically active compound or proportion of compounds is from 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the total composition. Suitable tablets are, for example, active substance (s) and known excipients, for example inert diluents (eg calcium carbonate, calcium phosphate or lactose), disintegrants (eg corn starch or alginic acid), binders (eg Starch or gelatin), lubricants (such as magnesium stearate or talc) and / or agents for slow release (such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate). Tablets may also include several layers.

Thus, coated tablets can be prepared by coating a core prepared similarly to the tablet with a material commonly used for coating tablets, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. . In order to achieve slow release or prevent incompatibility, the core may consist of multiple layers. Similarly, tablet coatings may consist of multiple layers, possibly for sustained release, using the above-mentioned excipients for tablets. Thus, syrups or elixirs containing the active substances or combinations thereof according to the invention may contain sweetening agents (e.g. saccharin, cyclamate, glycerol or sugars) and flavor enhancers such as vanillin or orange extracts. It may contain. They may also contain suspending aids or thickeners (eg sodium carboxymethyl cellulose), wetting agents (eg condensation products of fatty alcohols with ethylene oxide) or preservatives (eg p-hydroxybenzoates).

Liquid formulations are optionally made in conventional manner, using emulsifiers and / or dispersants, for example, isotonic agents, preservatives (eg p-hydroxybenzoate) or stabilizers (eg ethylenediamine tetraacetic acid). Alkali metal salts), and when water is used as a diluent, for example, an organic solvent can optionally be used as a solvating agent or dissolution aid and transferred to an injection vial or ampoule or a bottle for infusion.

Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol and packaging them in gelatin capsules. Suitable suppositories can be prepared by mixing with a carrier provided for this purpose, such as natural fats or polyethylene glycols or derivatives thereof. Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g. petroleum fractions), vegetable oils (e.g. peanut oil or sesame oil), mono- or polyfunctional alcohols (e.g. Ethanol or glycerol), carriers, such as natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic inorganic powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. sugar cane, lactose and glucose) , Emulsifiers such as lignin, sulfite waste liquor, methylcellulose, starch and polyvinylpyrrolidone, and lubricants such as magnesium stearate, talc, stearic acid and sodium lauryl sulfate.

The agent is administered by conventional methods, preferably by inhalation, in the treatment of asthma or COPD. In the case of oral administration, in addition to the above-mentioned carriers, tablets may also contain various additives such as starch, preferably potato starch and gelatin and the like, together with additives such as sodium citrate, calcium carbonate and dicalcium phosphate. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used simultaneously during the tableting process. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or coloring agents in addition to the excipients mentioned above.                 

The dosage of the compounds according to the invention naturally depends greatly on the route of administration and the disease to be treated. When administered by inhalation, the compound of formula 1 is characterized by high efficacy even at doses in the μg range. In addition, the compound of formula 1 can be used efficaciously in the µg range or more. Thus the dosage may, for example, be in the g range. In particular when administered by methods other than inhalation, the compounds according to the invention may be administered at higher doses (eg in the range of 1 to 1000 mg, although this dose does not include any limitations).

The following examples of formulations illustrate the invention without limiting its scope:

Examples of Pharmaceutical Formulations

(A) refined sugar

100 mg of active substance

Lactose 140mg

Corn Starch 240mg

15 mg polyvinylpyrrolidone

Magnesium Stearate 5mg

500 mg

A portion of the finely divided active substance, lactose and corn starch are mixed together. The mixture is screened and then wetted with polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, residual corn starch and magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

(B) refined sugar

Active substance 80mg

Lactose 55mg

Corn Starch 190mg

Microcrystalline Cellulose 35mg

15 mg polyvinylpyrrolidone

Sodium-Carboxymethyl Starch 23mg

Magnesium Stearate 2mg

400 mg

The finely divided active substance, part of corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the residual corn starch and water to form granules which are dried and screened. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and then the mixture is compressed to form tablets of suitable size.

(C) ampoule solution

   50 mg of active substance                 

   Sodium chloride 50mg

5ml water for injection

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The resulting solution is filtered to remove the exotherm and the filtrate is transferred to ampoules under sterile conditions, which are then sterilized and sealed by injection. The ampoule contains 5 mg, 25 mg and 50 mg of active substance.

(D) metered aerosol

Active substance 0.005

Sorbitan trioleate 0.1

Monofluorotrichloromethane and difluorodichloromethane 2: 3 about 100

The suspension is transferred to a conventional aerosol container equipped with a metering valve. Preferably 50 μl of suspension is delivered per spray. The active substance may optionally be metered in at higher doses (eg 0.02% by weight).

(E) solution (mg / 100ml)

333.3 mg of active substance

Formoterol fumarate 333.3mg

Benzalkonium Chloride 10.0mg

EDTA 50.0mg                 

HCl (1n) approx. PH 3.4

The solution can be prepared by conventional methods.

F) powder for inhalation

6 μg active substance

6 μg formoterol fumarate

Lactose Monohydrate About 25mg

Inhalable powders are prepared in a conventional manner by mixing the individual components together.

G) powder for inhalation

Active substance: 10 µg

5 mg of lactose monohydrate

Inhalable powders are prepared in a conventional manner by mixing the individual components together.

Claims (12)

A compound of formula 1, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates. Formula 1

In the above formula, A is

And

Double-bonded group selected from X ^- is an anion with a single negative charge, R ¹ and R ² may be the same or different and are a group selected from methyl, ethyl, n-propyl and isopropyl, which may be unsubstituted or substituted by hydroxy or fluorine, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ , R ⁷ is methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F, -CH ₂ -OH, -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O-COMe, -O-COEt, -O-COCF ₃ , -O-COCF ₃ , fluorine, chlorine or bromine. The method of claim 1, A

And

Double-bonded group selected from X ⁻ is an anion with a single negative charge, selected from chloride, bromide and methanesulfonate, R ¹ and R ² may be the same or different and are a group selected from methyl and ethyl which may be unsubstituted or substituted by hydroxy or fluorine, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine, A compound of formula 1, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, wherein R ⁷ is methyl, ethyl, methyloxy, ethyloxy, CF ₃ or fluorine. The method according to claim 1 or 2, A

And

Double-bonded group selected from X ^- is bromide, R ¹ and R ² may be the same or different and are a group selected from methyl and ethyl, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen, methyl, methyloxy, chlorine or fluorine, A compound of formula 1, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, wherein R ⁷ is methyl or fluorine. The method according to claim 1 or 2, A

And

Double-bonded group selected from X ^- is bromide, R ¹ and R ² may be the same or different and are methyl or ethyl, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and are hydrogen or fluorine, A compound of formula 1, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, wherein R ⁷ is methyl or fluorine. delete delete delete delete delete In a first step, a compound of formula 3 is reacted with a compound of formula 2 to yield a compound of formula 4, which is a compound of formula R ² -X wherein R ² and X are as defined in claim 1 or 2. And quaternized to obtain a compound of formula 1, wherein the compound of formula 1 is prepared. Formula 1

Formula 2

Formula 3

Formula 4

In Chemical Formulas 1 to 4, A, X ^- and groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be as defined in claim 1 or 2, R is chlorine or C ₁ -C ₄ -alkyloxy. The composition of claim 1, wherein X ⁻ is an anion selected from chloride, bromide, methylsulfate, 4-toluenesulfonate and methanesulfonate, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates. Compound of Formula 1. delete